Fatty acid amide hydrolase (FAAH) is the enzyme predominantly responsible for the catabolism of several fatty acid amides (FAA), including the endogenous cannabinoid N-arachidonoyI ethanolamine (anandamide), the sleep-inducing agent oleamide, the food-suppressing compound N-oleoylethanolamine (OEA), and the peripheral pain-suppressing agent N-palmitoylethanolamine (PEA). The creation of genetically engineered mice that lack this enzyme (i.e., FAAH(-/-) mice) has provided a powerful model to evaluate the function of this enzyme. These mice exhibit a CBI-mediated reduction in pain sensitivity, accompanied by substantial increases in endogenous anandamide levels compared to wild type mice. In the studies proposed in this application, we will evaluate the in vivo effects of a series of highly selective and reversible FAAH inhibitors. These FAAH inhibitors provide complementary tools to further our understanding of the physiological functions of the FAAH/FAA system. This project will employ pharmacological and behavioral methods to address three Specific Aims: 1) To determine the role of endocannabinoid-metabolizing enzymes in acute and chronic pain;2) To determine the role of endocannabinoid-metabolizing enzymes in cognition and emotion;and 3) To determine the role of endocannabinoid-metabolizing enzymes in morphine reward and withdrawal. RELEVANCE (See instructions): The endogenous cannabinoid system regulates a broad range of neurophysiological processes. Elucidation of the enzymes that regulate endogenous cannabinoids and their mechanisms of action may lead to the identification of new therapeutic targets for the treatment of human disorders such as chronic pain, depression, and anxiety.